Project Summary Chronic rhinosinusitis is a common inflammatory disease that affects a large portion of the U.S. population, resulting in poor quality of life for those affected and utilizing billions of dollars of health care resources. The etiology of CRS remains poorly understood but current evidence points to a dysregulation of the innate and adaptive immune system that results in persistent mucosal inflammation and microbial colonization. The central hypothesis of this proposal is that clinically relevant CRS endotypes defined by distinct inflammatory signatures are associated with changes to sinonasal microbiome community structure, composition, and function. We will test this hypothesis by analyzing a large prospectively enrolled cohort of healthy control and CRS patients. Specific Aim 1 will correlate inflammatory CRS endotypes previously identified by our research group using hierarchical cluster analysis with taxonomic changes to the sinonasal bacterial community. Aim 2 will complement findings from Aim 1 using an integrated metatranscriptomic approach to characterize both the host and bacterial transcriptome. This data will help determine the functional relevance of bacterial genes and transcripts present in CRS, and identify potential differences between endotypes, while also assessing related changes to the host transcriptome. We hypothesize that inflammatory CRS endotypes will be distinguished by variations not only in bacterial community structure and composition, but also in the function, metabolism, and transcriptional activity of resident bacteria. Findings from this study will provide insight into the mechanism of CRS and reveal previously unidentified associations between the sinus microbiota and different types of chronic mucosal inflammation in the sinonasal cavity.